Arsenicals, such as lewisite, diethylchloroarsine, diphenyl chlorarsine, and diphenyl cyanoarsine have been identified as potential war-threat agents, which could be used in chemical warfare. Topical exposure to these agents is known to result in severe cutaneous blistering and inflammation. In this application, we will test whether these arsenicals as listed above cause similar multiple cutaneous blistering and inflammatory effects in murine (haired but shaved) and mini-pig models as reported in humans. We will also investigate the molecular mechanisms by which these effects are manifested in these animal model systems. Our preliminary data indicate that in hairless murine model arsenicals by penetrating skin, rupture the cutaneous barrier functions as a consequence of disruption of proteins associated with tight junctions and water/glycerin transport. These effects are mediated mainly via activation of hippo signaling pathway protein, Yap besides others. Our data also show that the acute inflammation is mediated through the activation of unfolded protein response (UPR) signaling. UPR pathway is triggered by the arsenicals-dependent reactive oxygen species (ROS) production and activation of DNA damage response signaling. Based on these preliminary results, we will unravel whether crosstalk between these intricate signaling pathways results in the pathogenesis of painful blisters and inflammation. Based on these novel data, it is also tempting to investigate whether blocking these molecular targets by small molecules such as UPR signaling inhibitors also known as chemical chaperones, 4- phenylbutyric acid and salubrinal alone or in combination with arsenic chelator, British anti-lewisite (BAL) or antioxidant N-acetyl cysteine may intercept these effects. This will provide a molecular pathogenesis-based translational approach to develop effective interceptors/antidotes for blocking painful severe skin damage following cutaneous exposure to these chemicals. We are also proposing to test whether cutaneous exposure to these chemicals manifests systemic damage and whether topical application of these antidotes can prevent systemic effects of these chemicals. Three specific aims, each with their own milestones, are proposed to unravel the mechanism of pathogenesis by arsenicals in two animal models and to develop potential antidotes against these agents with defined window of their effectiveness. It is highly likely thatif found effective, the lead compounds based on their known toxicity profile and FDA approved use for other cutaneous blistering and inflammation-unrelated conditions can easily be approved. The outcome of the proposed research is likely to have a significant impact on human health protection in the unfortunate event of mass population exposure to this category of war-threat chemicals.